Advertisement

Molecular Biology Reports

, Volume 46, Issue 2, pp 1701–1707 | Cite as

Association between selected cholesterol-related gene polymorphisms and Alzheimer’s disease in a Turkish cohort

  • Gamze GuvenEmail author
  • Eren Vurgun
  • Basar Bilgic
  • Hasmet Hanagasi
  • Hakan Gurvit
  • Ebru Ozer
  • Ebba Lohmann
  • Nihan Erginel-Unaltuna
Original Article

Abstract

Numerous genetic evidence has pointed out that variations in cholesterol-related genes may be associated with an Alzheimer’s disease (AD) risk. We aimed to investigate the association between polymorphisms in several cholesterol-related genes [APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), SORL1 (rs2282649)] and AD in a cohort of Turkish patients. The study group consisted of 257 AD patients (mean age: 75.9 years ± 10.4) and 414 controls (mean age: 62.2 years ± 13.1). Genotyping was performed by quantitative real-time polymerase chain reaction using hydrolysis probes. Our results showed that the ‘TT’ genotype of CH25H rs13500 polymorphism was significantly more frequent in the AD group (p < 0.001) and individuals carrying the CH25H ‘T’ allele had an increased risk for AD (OR 3.07, 95% CI 2.13–4.44, p = 2.20e−09) independently from age, gender and APOE ε4 allele. Moreover, this risk was excessively increased (OR 14.04, 95% CI 6.99–28.23, p = 9.78e−14) in the presence of APOE ε4 allele. The ‘ins/ins’ genotype of APOC1 rs11568822 was significantly more frequent in the AD group compared to controls (p = 1.95e−08). However, this increased AD risk in ‘ins/ins’ carriers was found to be dependent on their APOE ε4 carrier status. No significant associations were found in allele and genotype distributions of APOA5, APOD, LDLR and SORL1 gene polymorphisms. Our results suggest that the association between APOC1 ‘ins/ins’ genotype and AD risk can be explained by linkage disequilibrium with the APOE locus. CH25H rs13500 polymorphism is associated with an AD risk in the Turkish population and CH25H might have a role in the pathogenesis of AD together with, and independently from APOE.

Keywords

Alzheimer’s disease Cholesterol metabolism Polymorphism Risk 

Notes

Acknowledgements

The authors thank all the patients and their families. Meltem Pak helped with obtaining the samples. This work was supported by the Research Fund of Istanbul University (Project No: TAB-2017-23218).

Compliance with ethical standards

Conflict of interest

The authors have no actual or potential conflicts of interest.

Supplementary material

11033_2019_4619_MOESM1_ESM.docx (43 kb)
Supplementary material 1 (DOCX 43 KB)

References

  1. 1.
    Auton A et al (2015) A global reference for human genetic variation. Nature 526:68–74.  https://doi.org/10.1038/nature15393 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Barbosa FA, de Labio RW, de Oliveira SRV, Minett T, Bertolucci PH, de Arruda Cardoso Smith M, Payao SL (2006) Apolipoprotein A-V gene polymorphism −1131T>C and Alzheimer’s disease. J Alzheimers Dis 10:365–369CrossRefPubMedGoogle Scholar
  3. 3.
    Beecham GW et al (2014) Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 10:e1004606.  https://doi.org/10.1371/journal.pgen.1004606 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bertram L et al (2000) Evidence for genetic linkage of Alzheimer’s disease to chromosome 10q. Science 290:2302–2303.  https://doi.org/10.1126/science.290.5500.2302 CrossRefPubMedGoogle Scholar
  5. 5.
    Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23.  https://doi.org/10.1038/ng1934 CrossRefPubMedGoogle Scholar
  6. 6.
    Ehehalt R, Keller P, Haass C, Thiele C, Simons K (2003) Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 160:113–123.  https://doi.org/10.1083/jcb.200207113 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gopalraj RK, Zhu H, Kelly JF, Mendiondo M, Pulliam JF, Bennett DA, Estus S (2005) Genetic association of low density lipoprotein receptor and Alzheimer’s disease. Neurobiol Aging 26:1–7.  https://doi.org/10.1016/j.neurobiolaging.2004.09.001 CrossRefPubMedGoogle Scholar
  8. 8.
    Helisalmi S et al (2004) Genetic variation in apolipoprotein D and Alzheimer’s disease. J Neurol 251:951–957.  https://doi.org/10.1007/s00415-004-0470-8 CrossRefPubMedGoogle Scholar
  9. 9.
    Kehoe P et al (1999) A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 8:237–245CrossRefPubMedGoogle Scholar
  10. 10.
    Ki CS, Na DL, Kim DK, Kim HJ, Kim JW (2002) Genetic association of an apolipoprotein C-I (APOC1) gene polymorphism with late-onset Alzheimer’s disease. Neurosc Lett 319:75–78CrossRefGoogle Scholar
  11. 11.
    Leduc V et al (2015) HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer’s disease in a three cohorts study. Mol Psychiatry 20:867–873.  https://doi.org/10.1038/mp.2014.81 CrossRefPubMedGoogle Scholar
  12. 12.
    Lee JH et al (2007) The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort. Arch Neurol 64:501–506.  https://doi.org/10.1001/archneur.64.4.501 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Li Y et al (2008) SORL1 variants and risk of late-onset Alzheimer’s disease. Neurobiol Dis 29:293–296.  https://doi.org/10.1016/j.nbd.2007.09.001 CrossRefPubMedGoogle Scholar
  14. 14.
    McKhann GM et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:263–269.  https://doi.org/10.1016/j.jalz.2011.03.005 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Morris MC et al (2003) Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 60:194–200CrossRefPubMedGoogle Scholar
  16. 16.
    Nilsson SK, Heeren J, Olivecrona G, Merkel M (2011) Apolipoprotein A-V: a potent triglyceride reducer. Atherosclerosis 219:15–21.  https://doi.org/10.1016/j.atherosclerosis.2011.07.019 CrossRefPubMedGoogle Scholar
  17. 17.
    Notkola IL et al (1998) Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 17:14–20.  https://doi.org/10.1159/000026149 CrossRefPubMedGoogle Scholar
  18. 18.
    Papassotiropoulos A et al (2005) Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer’s disease. Neuro-degener Dis 2:233–241.  https://doi.org/10.1159/000090362 CrossRefGoogle Scholar
  19. 19.
    Pappolla MA et al (2003) Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61:199–205 doi.  https://doi.org/10.1212/01.Wnl.0000070182.02537.84 CrossRefPubMedGoogle Scholar
  20. 20.
    Petit-Turcotte C et al (2001) Apolipoprotein C-I expression in the brain in Alzheimer’s disease. Neurobiol Dis 8:953–963.  https://doi.org/10.1006/nbdi.2001.0441 CrossRefPubMedGoogle Scholar
  21. 21.
    Picard C et al (2018) Alterations in cholesterol metabolism-related genes in sporadic Alzheimer’s disease. Neurobiol Aging 66:180e181–180e189  https://doi.org/10.1016/j.neurobiolaging.2018.01.018 CrossRefGoogle Scholar
  22. 22.
    Poduslo SE, Neal M, Herring K, Shelly J (1998) The apolipoprotein CI A allele as a risk factor for Alzheimer’s disease. Neurochem Res 23:361–367CrossRefPubMedGoogle Scholar
  23. 23.
    Poirier J, Hess M, May PC, Finch CE (1991) Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Brain Res Mol Brain Res 11:97–106CrossRefPubMedGoogle Scholar
  24. 24.
    Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32:461–493 doi.  https://doi.org/10.1146/annurev.genet.32.1.461 CrossRefPubMedGoogle Scholar
  25. 25.
    Rassart E, Bedirian A, Do Carmo S, Guinard O, Sirois J, Terrisse L, Milne R (2000) Apolipoprotein D. Biochim Biophys Acta 1482:185–198CrossRefPubMedGoogle Scholar
  26. 26.
    Reiman EM et al (2007) GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron 54:713–720.  https://doi.org/10.1016/j.neuron.2007.05.022 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Riemenschneider M et al (2004) Association analysis of genes involved in cholesterol metabolism located within the linkage region on chromosome 10 and Alzheimer’s disease. Neurobiol Aging 25:1305–1308.  https://doi.org/10.1016/j.neurobiolaging.2004.01.001 CrossRefPubMedGoogle Scholar
  28. 28.
    Rodriguez E, Mateo I, Llorca J, Sanchez-Quintana C, Infante J, Berciano J, Combarros O (2006) Brief research communication - No association between low density lipoprotein receptor genetic variants and Alzheimer’s disease risk. Am J Med Genet B 141B:541–543.  https://doi.org/10.1002/ajmg.b.30341 CrossRefGoogle Scholar
  29. 29.
    Rogaeva E et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177.  https://doi.org/10.1038/ng1943 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Scacchi R et al (1999) Plasma levels of apolipoprotein E and genetic markers in elderly patients with Alzheimer’s disease. Neurosci Lett 259:33–36CrossRefPubMedGoogle Scholar
  31. 31.
    Shibata N et al (2006) Association studies of cholesterol metabolism genes (CH25H, ABCA1 and CH24H) in Alzheimer’s disease. Neurosci Lett 391:142–146.  https://doi.org/10.1016/j.neulet.2005.08.048 CrossRefPubMedGoogle Scholar
  32. 32.
    Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460–6464CrossRefPubMedGoogle Scholar
  33. 33.
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90:1977–1981CrossRefPubMedGoogle Scholar
  34. 34.
    Wollmer MA (2010) Cholesterol-related genes in Alzheimer’s disease. Biochim Biophys Acta 1801:762–773.  https://doi.org/10.1016/j.bbalip.2010.05.009 CrossRefPubMedGoogle Scholar
  35. 35.
    Wollmer MA et al (2007) Association study of cholesterol-related genes in Alzheimer’s disease. Neurogenetics 8:179–188.  https://doi.org/10.1007/s10048-007-0087-z CrossRefPubMedGoogle Scholar
  36. 36.
    Xu C, Bai R, Zhang D, Li Z, Zhu H, Lai M, Zhu Y (2013) Effects of APOA5 −1131T>C (rs662799) on fasting plasma lipids and risk of metabolic syndrome: evidence from a case-control study in China and a meta-analysis. PLoS ONE 8:e56216.  https://doi.org/10.1371/journal.pone.0056216 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhou Q et al (2014) Association between APOC1 polymorphism and Alzheimer’s disease: a case–control study and meta-analysis. PLoS ONE.  https://doi.org/10.1371/journal.pone.0087017 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
  2. 2.Department of Medical BiochemistryOkmeydani Training and Research HospitalIstanbulTurkey
  3. 3.Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
  4. 4.Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  5. 5.DZNE, German Center for Neurodegenerative DiseasesTübingenGermany

Personalised recommendations